6th CPH assessment training workshopMay 2014

Process validation

Talk points Objectives of review of quality(CMC) data- reminder Process validation, definition and current approaches Role of dossier assessment in process validation Risk assessment as part of process validation Validation scheme: Monitoring and Sampling Specific topics: Blend uniformity and validation of compression step Process validation: other dosage forms Process validation commitment Retrospective validation Summary: How to review protocol and report

Reminder

Objectives of assessment of quality partTo provide the highest assurance that all production batches (unit

doses) will be consistently efficacious as the clinical batch(es)To reduce risk to safety via the highest assurance of acceptable and

consistent quality of the product and its components

Process validation

Process validation

The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. (FDA)

Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets predetermined specifications and quality characteristics. (WHO)

The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.(EMA)

Process validationTraditional vs new paradigm

Post approval changes/chan

ge controls/risk

analysis

Development- Basic

Process validation- 3

batches

Pilot batch manufacturing

Enhanced-Development and

process qualification

Control Strategy

Continuous and extensive monitoring of CQAs and CPPs for each production

batch

ICH Q9 and Q10

ICH Q8, QbD

Latest guidelinesFDA, January 2011 WHO, Revised Annex 7 of

WHO GMP guide (draft for comment)

EMA, February 2014

Continuous process verification (CPV)

Continuous process verification (CPV)

Alternative approaches: -Traditional approach-Continuous process verification-Hybrid approach

Process design and Initial validation (process qualification- PPQ) are initial phases of CPV

Process design and initial validation (initial process verification) are initial phases of CPV

CPV protocol to be supported by extensive development information and lab or pilot scale data. Executed on each production batch

No mention of number of batches for initial process performance qualification/validation (rather must be justified based on overall product and process understanding)

Mentions data on at least three pilot or production batches collected as part of process design

Number of batches specified for traditional approach- minimum of three production batches unless other wise justified

Types of process validation and dossier requirements

Prospective validation Concurrent validation Retrospective validation

Protocol reviewed and accepted, Product PQD; OR Protocol executed before submission or PQ

Protocol reviewed and accepted, Product PQD

Protocol does not need to be submitted

Execute and finalize process validation on the first three production batches

Execute and finalize process validation on the first three production batches

Prepare product quality review report on already manufactured production batches

Commercial batches to be released only after satisfactorily conclusion of process validation on three batches

Each validation batch can be validated and released.Applicable for low demand products (such as NTDs, orphan drugs or other seasonal products)

Applicable for submissions meeting criteria for established products as described in Annex 4, TRS 970

Process validation- Role of assessment

Design qualification

Operational qualification

Performance qualification

Process validation

GMP

Dossier

Process validation phases

Pre-validation phaseProtocol Preparation

Information from product development studies (identification of critical attributes)

Information from primary/clinical manufacturing

(scale up information) Process risk

assessment information

(identification of critical steps)

Validation phaseProtocol execution

Post valdn phase:Review of process, deviations, failures,

need for improvement, scale up etc…

Includes demonstration of content uniformity of the

clinical batch

Risk assessment

Part of process development and protocol preparationRisk matrix- usually as part of process development

Critical quality attributes (CQA) vs processing stages, e.g. dissolution vs granulationCQA vs critical process parameters, e.g., dissolution vs kneading time

Failure mode analysis- usually as part of process validation To identify critical attributes, processes and parameters

Informed validationTo establish control strategy

Example: risk matrix for low dose capsule (CQA vs process stages)

  Sifting/sizing blending lubrication Capsule filling

Assay  Low Medium Medium Medium

Content uniformity

High High High High

Dissolution Low Low High Low

Stability Low Low Low Low

Process steps to be validated

All steps that are generally considered critical (medium and high risk steps) should be monitored/scrutinizedby summarizing actual process parameters applied and

observations recorded e.g. sifting stage, wet and dry granulation stages

observations serve as feedback for future refinement of process parameters

In addition, where feasible, sampling and testing should be performed

e.g. drying, mixing steps, compression, filling results measure effectiveness and consistency of the immediate as well as

preceding steps- e.g. final blend characteristics are mainly shaped by wet/dry granulation process

Validation scheme- example

Processing steps Critical parameters  Validation  scheme

Dispensing Weight checks Monitored

Sifting Mesh size Monitored

Wet Granulation and drying Amount and addition rate of granulating agent, mixing speed, time, as well as sequence of events

Monitored, Drying uniformity to be tested

Dry Granulation Slugging /compaction parameters

Monitored only or Monitored and sampled?

Blending mixing speed, time Monitored; Blend uniformity to be established

Lubrication mixing speed, time Monitored; Blend uniformity from mixer and bulk container

Compression Initial set up parameters,speed, applied pressure,

Monitored; Several samples to be sampled and tested for IPQC parameters

Fluidized bed coating Spray rate, inlet and product temp, etc…

Monitored; appearance, weight gain and full testing

Primary packaging, protocol requested on case by case basis

Sealing temperature, speed Monitored; leak test

Monitoring- Example:Compaction

Any comment vis à vis the difference between BMR set range and actual applied inputs?

BMR Set parameters

 Batch 1 Batch 2 Batch 3

e.g. of parameters

Cycle 1 Cycle 2 Cycle 1 Cycle 2 Cycle 1 Cycle 2

Roller speed (RPM)

8-15 10 10 10 10 10 10

Roller pressure (Bars)

40-60 41-42 42-43 41-43 41-42 41-42 41-43

Vertical feed screw (RPM)

50-100 75 75 75 75 75 75

Horizontal feed screw (RPM)

10-20 15 15 15 15 15 15

Example: Monitoring and sampling:Drying

Monitoring Set parameter Observation

Batch X Batch Y Batch Z

Inlet temperature 60+/-10oC 62-65 52-63 52-60

Outlet temp 29-44 31-47 28-36

Total drying time (min) (for information)

65 65 80

Sampling and testing

Spec Batch X Batch Y Batch Z

Location 1 0.75-2.25% 1.54 1.53 1.70

Location 2 1.94 2.01 1.80

Location 3 2.03 1.30 2.05

Location 4 1.89 1.87 2.20

Blend uniformityEarly check for content uniformity of the final dosage form

Uniform blend with good flow and

compressibility characteristics

Compression with optimum conditions

Tablets meeting criteria for uniformity

of dosage units

Note: Blend uniformity is a routine test for low dose products (i.e. active load <=5% or 5mg)

Blend uniformity- Sampling location and method

Sampling location -usually predetermined as part of qualification of the mixer (i.e. mostly GMP issue)But, in the dossier, we at least check if periphery, center

positions and various other positions are consideredSamples from each location are usually taken in triplicate

Samples should also be taken from the blend container- to evaluate impact of transfer important for low dose products and particularly for DC

processed blend Sampling should be done consistently and in away that does not

disturb the bulk blend state – such aspects (e.g. type of sampling thief used) are better addressed at the time of inspection

Blend uniformity- Sample size

What is an acceptable amount for samples taken at each location? Normally 1-3 time of the FPP unit dose weight

Blend uniformity- acceptance criteria

Commonly used criteriaIndividual assays: 90.0-110.0% of label claim, RSD NMT 5.0%

Less commonIndividual assays:90.0-110.0% of the mean value, RSD NMT 5.0%

In this case, setting mean = 95.0-105.0% of the label claim appears reasonable

Rarely (in case of very low dose products)Individual assays: 85.0-105.0% of the label claim/mean value, RSD:

NMT 5.0%May be acceptable provided that uniformity of dosage units is

satisfactorily demonstrated on tablets/capsules manufactured from blend lot with close to limit blend uniformity results

Sampling and testing plan- Lubrication- example

missing parameter?Do you agree with the acceptance criteria?

Sample location

Sample size Sample analysed

Tests Acceptance limits

Lubrication 10 position from Octagonal blender and blend container

850-2550mg in triplicate

10 Individual samples

Blend uniformity

Mean: 95.0-105.0%, individual: 90-110%, RSD: NMT 5%

Samples from top, middle and bottom

50gm Composite samples

Complete analysis as per routine blend spec

As per blend spec

Particle size distribution, bulk and tapped density

For information

What are the minimum tests we 

expect to see in blend spec?

Acceptable?

Compression Good compression outcome is a measure of (it depends on):-

Granule/powder mix propertiesbulk and tapped density-granulationparticle size and particle size distribution-granulationmoisture content- dryingextent of lubrication- lubrication time

Machine and tooling attributes appropriate selection and adequate lubrication of punches and dye machine speed applied compression pressure

Compression – Sampling frequency and sizedepends on the length of the run time/ batch

sizewe expect frequent sampling than the normal IPQC

frequencythe number of tablets/capsules taken should be greater

than those taken during a normal IPQC sampling

Compression- Challenge studies

Certain variations in compression speed and hardness than the target set points may happenwhat would be the impact of such

variations?speed affects dwell time- which

intern affects several tablet parameters (thickness, hardness, as well as weight variation)

Therefore, robustness should be demonstrated

C. Morten, PIAT programme, University of Manchester

Extensive sampling- example(there are several other approaches)

IPQC testing schedule Normal production batch Validation batches

48 station machine, batch size of 170,000 tabs, target speed 25rpm

Group weight and appearance, every 30 minutes; others every 1 hour (at least 3 times)

About 300 tablets About 300 tablets

All in process parameters at start, middle and end of compression (different hopper fill levels)

-About 360 tablets

Additional samples at high, low speed; at high and low hardness levels

- About 480 samples

Total number of tablets sampled

300 tablets 1140 tablets

How to demonstrate consistency?

3 sigma process

e.g. 4 sigma process

Process validation-oral solutionsValidation focuses on

mixing time and conditions to clear solution, if deemed relevant bulk liquids: pH, specific gravity, clarity of solutions; assay

filling process filled units:- Volume/Wt variation and as per FPP specs

Protocol with commitment is acceptable at the time of review

Process Validation- Oral suspensionsFocuses on

API micronization processes (if applicable)colloidal milling process (as applicable), homogenization filling

Viscosity, fill volume/weight variation, Other critical attribute that may be affected by filling process?Other parameters as per FPP spec including, PSD, pH, dissolution,

Protocol with commitment is acceptable at the time of review

Process validation- sterile productsProducts mfd by Terminal sterilization

Products mfd by Aseptic processing

Container and component sterilization and depyrogenation

- Depyrogenation by tunnel depyrogenator (e.g. ampoules) or washing (e.g. rubber stoppers, plastic bottles)

- Depyrogenation by washing- for stoppers, seals, accessories*

- Validation of steam sterilization – for stoppers, seals, accessories*

- Dry heat sterilization and depyrogenation- for glass vials or ampoules*

Process validation- sterile products-Contd

Products mfd by Terminal sterilization

Products mfd by Aseptic processing

Product sterilization Terminal sterilization bySteam sterilization, radiation or ETO (as applicable)*

Filter validation (as part of dev’t pharm)

Process simulation - Media fill

Full batch processing (other aspects of the mfg process, e.g. valdn of bulk prepn, filling and sealing quality)

3 production batches mfd at proposed scale

3 production batches mfd at proposed scale (commitment may also be accepted).

*validation should be on three runs to demonstrate reproducibility.

Dissolution profile comparison with clinical/BE batch- solids and suspensions (as part of process validation)

A good check point to verify performance relative to the biobatchAll validation batches should be profiled in the routine

media on 12 units, using time points as used for biobatchComparison with historical biobatch profile, with

calculation of f2 (as necessary), should be performed and results discussed

Check if the protocol includes adequate instruction/provision

Matrixing/bracketing approach

Multiple strengths of same product (common blend)until stages of final granules: 3 consecutive batches of the common

blend (instead of 3 separate blend batches for each strength)compression: 3 consecutive batches of each strength

Primary packaging of tablet/capsule productsblistering of hygroscopic or moisture sensitive products

however should always be individually validated

Process validation- commitmentAs described in Annex 4, TRS 970, applicants are

not expected to have process validation data before PQIn this case satisfactory PV protocol (PVP) and

appropriately worded commitment are essential PVP or signed commitment letter should clearly indicate

the need for prospective validation as finalized on three consecutive production batches, unless other wise justified.

Retrospective validation for established products

Generally acceptable if condition described in Annex 4, TRS 970 (generic guide), are met.

Tries to demonstrate process effectiveness and consistency via trend analysis:extent of deviationsextent of OOS or OOTextent of batch rejectionextent of product complainsextent of changes/ improvements introducedSee Appendix 2 of Annex 4, TRS 970

Review of protocol- main aspects to check

Scope of the validation (type, batch size, reason)- do they reflect the planned validation? Highest batch size to be validated?

Major equipments identified (in line with BMR) and a provision for recording their Q status included?

Reference to current master production record included? Summary of critical steps identified? is this convincing ? Monitoring and sampling plan provided?- Do you agree with the

steps monitored/sampled? Sampling schedule, schematics, tests and acceptance criteria, as well

as current specification codes included ? Are these acceptable?

Review of protocol- main aspects to check-contd

For solid orals: final blending, compression/encapsulation, coating stages must be adequately sampled and tested. Are these being reflected?

Blend uniformity: Sampling schemes and blend uniformity acceptance criteria specified? Are these acceptable?

Compression/encapsulation at lower, target and upper speeds included?

Provision for performance of dissolution profile testing and comparison with the biobatch included?

Appropriate commitment (prospective validation on first three consecutive batches mentioned) provided?

Protocol reference and version number included in QIS?

Review of validation report Is the reported data relevant for the proposed manufacturing process and

scaleequipment used, process parameters applied

All critical steps adequately monitored/sampled?Level of sampling and size are acceptable?All results within acceptable limits? Particular trend?Deviations appropriately evaluated and discussed? Is the overall process in sufficient control? Is there any thing that should

be improved or refined for future production batches